Extracellular superoxide dismutase haplotypes are associated with acute lung injury and mortality.
BACKGROUND
Extracellular superoxide dismutase (EC-SOD) is a potent antioxidant that plays an important role in controlling oxidant-mediated stress and inflammation. High levels of EC-SOD are found in the lung. Acute lung injury (ALI) frequently occurs in patients with infection, and levels of EC-SOD have been shown to modulate severity of lung injury in transgenic animal models of endotoxemia-induced ALI. An R213G single nucleotide polymorphism (SNP) has been shown to alter levels of EC-SOD and patient outcomes in chronic obstructive pulmonary disease (COPD) and ischemic heart disease.


OBJECTIVE
To determine genetic variation in the promoter and EC-SOD gene and to examine whether EC-SOD haplotype blocks are associated with clinical outcomes.


METHODS
We sequenced the EC-SOD promoter and gene to determine genetic variation and linkage disequilibrium (LD) patterns in a European American population. Two separate patient populations with infection-associated ALI were also evaluated to determine whether EC-SOD haplotypes were associated with clinical outcomes.


RESULTS
Sequencing resulted in the identification of 28 SNPs with relatively strong LD and 1 block consisting of 4691-5321-5360-5955-5982. This specific block was shown to be protective in two separate patient populations with infection associated ALI. In particular, patients with a GCCT haplotype had a reduced risk of time on the ventilator and mortality.


CONCLUSIONS
These results indicate that a GCCT haplotype may reduce inflammation in the lung, thereby decreasing the severity of lung injury and ultimately protecting patients from mortality associated with infection-induced ALI.
Arcaroli
John J
JJ
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado at Denver, and Health Sciences Center, Denver, Colorado, USA.
Hokanson
John E
JE
Abraham
Edward
E
Geraci
Mark
M
Murphy
James R
JR
Bowler
Russell P
RP
Dinarello
Charles A
CA
Silveira
Lori
L
Sankoff
Jeff
J
Heyland
Daren
D
Wischmeyer
Paul
P
Crapo
James D
JD
D055371:Acute Lung Injury / Q000235:genetics* / Q000401:mortality*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D003120:Colorado / Q000453:epidemiology; D005260:Female; D014644:Genetic Variation; D015894:Genome, Human; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D013482:Superoxide Dismutase / Q000235:genetics*; D016019:Survival Analysis; D044465:White People / Q000706:statistics & numerical data
D015415:Biomarkers; C441642:SOD3 protein, human; D013482:Superoxide Dismutase